Atherosclerotic coronary disease is the most common cause of mortality in the United States. Mouse models of atherosclerosis have been useful for studying the pathogenesis of atherosclerosis and for the identification of atherosclerosis modifier genes by testing candidate genes through their under or over expression. Additionally, unbiased genetic methods have been used to map the loci of mouse genes that alter atherosclerosis susceptibility; and, the successful identification of a couple of these genes has now been reported. By the use of a strain intercross, we identified the Ath24 and Ath26 loci, which contain genes modifying atherosclerosis susceptibility in female and male mice, respectively. Through the use of gene expression profiling in macrophages derived from the strain intercross cohort, we found genetic loci that are associated with the levels of specific transcripts; and, we identified the genes whose expression was best correlated with atherosclerosis. Remarkably, the best correlated gene in each sex mapped to the corresponding Ath locus for that sex. We propose to confirm the identity of the Ath24 and Ath26 genes, and perform studies to gain insight into their mechanism of action. We also propose to see if genetic variation in the human orthologs of these genes is associated with coronary artery disease (CAD). We present preliminary data that human genetic variation in the top Ath24 and Ath26 gene candidates are in fact associated with CAD. PUBLIC HEALTH RELEVANCE: Atherosclerotic coronary disease (CAD) is the most common cause of mortality in the United States. The proposed studies may identify human genes and pathways not previously recognized to play a role in atherosclerosis. These may lead to diagnostic tools, novel drug targets, and therapies to prevent or treat CAD. Thus, the proposed studies address a significant health concern and offer hope for new modes of risk assessment and prevention.